In a joint study with investigators in Laboratory of Molecular Biology, NCI and Institut National de la Recherche Agronomique (INRA), France, we attacked the problem of protein structure classification, with the goal of improving automated methods for recognizing and classifying protein domains in three dimensional structures. Domains are thought to be the building blocks of complex structures, and often determine protein function. We have recently shown that two distinct structure similarity measures (VAST and SHEBA) can obtain at best about 75-80% agreement with a standard manually curated protein classification (SCOP), calling into question the existence of sharp boundaries between protein "folds". We have published a further analysis of "C-class" or alpha/beta protein domains, by hierarchically clustering domains based on measured structural similarity by three different methods (VAST, SHEBA and DALI). We found that automatic classifications differ little from each other, relative to their overall differences from SCOP. One implication is that identification of conserved motifs or cores may be necessary before identifying domain classes. We have developed three related algorithms for defining domains based on recurrence of similar domains in other structural contexts in other proteins in the PDB. Starting with a list of similar fragments to the query structure, the algorithms determine whether to divide the query into one or multiple domains, and the domain boundaries. Some domains appear to be discontinuous within the structure, indicating a possible evolutionary insertion of the underlying DNA sequence corresponding to the inserted domain. Testing and validation of these algorithms is complete and a manuscript has been submitted. With an investigator in the Division of International Epidemiology and Population Studies,Fogarty International Center, we have developed a phenomenological model of Plasmodium/redblood cell dynamics moderated by host immune and erythropoietic responses. All stages of theparasite's intra-host lifecycle are incorporated in the model, along with plausible humanimmune responses. At present we are studying how regulation of parasitmia by both host andparasite factors affects transmissibility of the parasite to its mosquito vector;in particular,we are studying the difference in transmission strategies between the different Plasmodiumspecies which cause human disease. A talk describing how host regulating of parasitemia canaffect transmissibility of the diseases was presented at 2009 Annual Meeting of the AmericanSociety of Tropical Medicine and Hygiene (December 2009). A poster about this work was presentedat the 2010 Gordon Research Conference on the Biology of Host-Parasite Interactions. Working with experimental investigators in the Laboratory of Malaria and Vector Research (LMVR),National Institute of Allergy and Infectious Diseases, we are studying the rate of conversion of asexual forms of malaria parasites to their sexual forms (which are the forms taken up by themosquito vectors). In particular, we are interested if this rate changes over time. Populations ofparasites of the species Plasmodium falciparum are being cultivated in cultures of red blood cellsby personnel of LMVR in order to collect time series data in the ratio of sexual forms to asexual forms. With consortium of investigators from (1) Laboratory of Neurotoxicology, National Institute ofMental Health, (2) Laboratory of Integrative Biophysics, Child Health and Human Development (NICHD),(3) Cell Biology and Metabolism Program, NICHD, (4) Laboratory of Pathology, National Cancer Institute,(5) Computational Bioscience and Engineering Laboratory, Division of Computational Bioscience, Centerfor Information Technology, (6) Biomedical Engineering and Physical Science Shared Resource, NationalInstitute of Biomedical Imaging and Bioengineering, we are working of a model of the thermal and fluidtransport processes that occur in the operation of expression microdissection (xMD). This is a newlydeveloped method of extraction large number of cells from a tissue sample which is very promising forpathology, but both basic engineering development and a better theoretical understanding of itsoperations are needed before this technology can be fully exploited, either in an NIH core facilityor for commercial distribution. Development of xMD is being support by an NIH Director's ChallengeInnovation Award for 2009-2010. In a project with investigators of NIMH we study cortical networks reconstructed from multiple-electrode recordings from in-vitro neural network preparations, and from in-vivo recordings from a pre-motor cortex of an awake macaque monkey. The reconstructions are performed using the algorithm that we developed previously, a work published in PLoS Computational Biology in 2009. We compare these network architectures to human brain networks obtained using diffusion spectrum imaging (DSI) and fMRI, as well as a number of other (non-neural) weighted complex networks, like scientific collaboration networks, airline networks, communication networks etc. Our study reveals novel and robust weight organization in the networks with neural origin that is not present in other networks. Simulations indicate that such network architecture can be obtained using local learning rules. A manuscript describing this work is in preparation and will be submitted in 2010. In a continuing project with investigators in the Program on Pediatric Imaging and Tissue Sciences (PPITS), NICHD we conduct a theoretical study of the observed skewed and heavy-tailed distribution of the axonal diameters. We show that the observed distribution can arise when optimizing the information transfer through axonal bundles and a manuscript describing this work is in preparation. A book chapter titled "Statistical Issues in DT-MRI" has been written that, among other, describes the work done in collaboration with this group. It is part of the Oxford University book "Diffusion MRI: Theory, Methods and Applications", 2010. In another project with Section on Analytical and Functional Biophotonics,PPITS, NICHD and MSCL/DCB/CIT, related to the development of the optical imaging techniques we derived theoretical predictions for the effects of the photon-fluorophore interactions in the time-gated optical imaging techniques. A software tool written in python (Fluorofit) implements this model and enables efficient estimation of the relevant biological parameters. This tool has been made available to the above collaborators.